Introduction

In the UK, it is estimated that about 112,000 children and young people suffer with epilepsy, which results in being one of the most common long-term illnesses.¹ Epilepsy is a condition characterised by the brain sending frequent electric signals from brain cells (neurons) or specific regions of the brain being hyperactive. This can lead to frequent involuntary movements or convulsions of the whole body known as seizures. As a result, this can cause a person to lose consciousness.²

Although it can arise at any age, many cases of epilepsy are diagnosed from an early childhood and last well until adulthood. The cause of epilepsy is brought on by genetics, metabolic disorders, or brain injury and/or damage - however, in certain cases, there is a lack of known explanation for epilepsy. There are many distinctive types of epilepsy, including but unlimited to:³ 

• Dravet syndrome: A rare form of genetic epilepsy that begins in infancy, which does not react well to seizure medications and results in developmental delays
• Lennox-Gastaut syndrome: Characterised by repetitive seizures, which may lead to permanent brain damage
• Rasmussen syndrome: A disorder that is linked to gradually deteriorating neurological disorders and convulsions in children
• Childhood absence: Without warning, this type of epilepsy causes “absent” seizures - this entails the child staring blankly or spacing out, resulting in losing awareness around their surroundings for a while
• Febrile seizures: Seizures which occur when a child has a high temperature

Medications and cannabinoids

Since overactive neurons cause epileptic seizures, anti-epileptic medications (AEDs) either prevent seizures from happening again or lessen their frequency and intensity by reducing the neuronal activity. However, medication may not always be effective in preventing seizures. Other treatment interventions such as surgery or vagus nerve stimulation should be taken into consideration in these situations. 

In severe or rare cases of epilepsy where the typical treatment plans do not work, cannabidiol (CBD) has been introduced as a therapeutic treatment option for paediatric patients. CBD is a type of medical cannabis, which has been researched to relieve severe epileptic symptoms. This is not to be confused with tetrahydrocannabinol (THC), a compound in cannabis that gives users the feeling of being “high.” 

At present, Epidyolex is the only CBD approved by the National Institute for Health and Care Excellence (NICE) for the treatment of epilepsy, in particular for patients who have Dravets syndrome or Lennox-Gastaut syndrome.⁴ It does not contain a trace of THC; instead this medication comprise of a purified form of CBD, and only a selection of individuals are able to receive a prescription by their doctors. The guidelines that are applicable to adults and children with these disorders suggest patients who are two years of age or older, and, for whom,  two or more epilepsy medications have failed to appropriately control their seizures.

Mechanism of CBD in epilepsy management

Scientists have discovered that the exact mechanism of CBD causing seizures remains unclear. However, they believe that CBD reduce seizure activity through moderating the ability of neurons to respond to stimuli (referred as neuronal excitability) and affect neurotransmitter signalling. To clarify, it has recently been discovered that lysophosphatidylinositol (LPI) is a molecule that CBD prevents from sending signals in the hippocampus (a region that plays a significant role in memory and learning). LPI, which is present in neurons in the brain, is believed to enhance nerve signals as part of normal function but can be manipulated by diseases to encourage seizures. By balancing the brain’s excitatory and inhibitory signals, CBD was found to be blocking an overstimulation of LPI to stabilise the overall brain function.⁵

Inflammation

In addition, it is well known that CBD impacts the receptors of the endocannabinoid system known as CB - this particular system is involved in the peripheral and central nervous system, and controls a wide variety of critical physiological functions such as appetite, memory, movement, and pain. Whilst CB1 receptors are involved in the pain pathways of the nervous system, CB2 receptors affect the immune system.⁶ CBD is unable to bind directly to CB1 and CB2 due to low binding affinity - therefore, this component increases the activity level of the endocannabinoid system by interacting with other receptors such as TRPV1 and GPR55, causing a reduced inflammation. Clinical evidence has indicated that brain inflammation contributes to the onset of seizures. By targeting these specific receptors, in particular CB2, the indirect modulation of CBD helps to restore balance in the body.⁷

Seizure frequency

The severity and frequency of seizures can also be reduced by CBD, as it promotes an activity of gamma-aminobutyric acid (GABA) which interacts with TRPV1 and GPR55. This particular neurotransmitter is dubbed to have a “calming effect” by blocking specific signals. An increase in GABA activity by CBD can reduce a neuronal overactivity which is known to trigger seizures.⁸

Potential side effects of CBD 

Although CBD helps with the various syndromes of epilepsy, there are some potential side effects that may arise when taking CBD, although not everyone will experience it. This may include the following:⁹ 

• Fever or a high temperature
• Diarrhoea
• Feeling nauseous/vomiting
• Drowsiness, sleepiness, or a lack of energy
• Decreased appetite 
• Weight loss 

Some individuals may also experience serious side effects, including: 

• Suicidal thoughts or tendencies
• A blood test that indicates a high liver enzymes, which can indicate signs of liver injuries

Current limitations

Research surrounding the effects of CBD in epilepsy is still ongoing, with many variations of CBD going through clinical trials. At present, the main limitations comprises of the various side effects experienced by users, particularly in appetite, increased liver enzymes, and suicidal thoughts. There is therefore a strong need for more longitudinal studies to assess the effectiveness and safety of CBD in paediatric patients, particularly for the currently approved types of epilepsy syndromes. A recent systematic review has demonstrated that long-term use of CBD induces significant alterations in the activity of the brain; however, the mental (cognitive) and psychological effects in children, in patients with psychiatric disorders or repilepsy are unclear.¹⁰ Due to the lack of long-term data, doctors are hesitant to recommend CBD for extended periods of time. 

The standardisation and optimisation of dosage present another difficulty. Although CBD has demonstrated efficacy at specific dosages, it is difficult to optimise the appropriate dosage based on an individual's needs; dosage varies greatly depending on weight, age, type of epilepsy, and individual metabolism. Since too little CBD may be ineffective and too much can raise the risk of side effects, it is crucial to determine the ideal dosage. Additionally, because CBD might change how antiepileptic medications are metabolised, it may cause complicated drug interactions in paediatric patients currently undertaking these treatments, which requires extra monitoring or dosage changes.⁹

Summary

Epilepsy is one of the long-term illnesses in children across the UK. Characterised by seizures and convulsions, this condition comprises different types; some may be drug-resistant such as Dravet and Lennox-Gastaut syndromes, requiring a new treatment option in the management of seizures.

CBD is a type of medical cannabis, which has been researched to relieve severe epileptic symptoms. By enhancing relaxing neurotransmitters, promoting anti-inflammation, and acting through indirect pathways to stabilise neuronal activity, CBD has shown promise in reducing the frequency and severity of seizures. However, challenges remain with finding the ideal dosage and in reducing the severe side effects such as gastrointestinal issues and suicidal tendencies. With further research, CBD presents a novel option for the management of epilepsy.